Hydrogen cyanide

Epidemiological data

Administrative data

Endpoint:

epidemiological data

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Experimental data was reviewed by the ECETOC Task Force, author of the JACC Report No. 53, "Cyanides of Hydrogen, Sodium and Potassium, and Acetone Cyanohydrin (CAS No. 74-90-8, 143-33-9, 151-50-8 and 75-86-5)", 2007. The report is a weight of evidence approach to an extensive body of literature, much of which was undertaken prior to development of guidelines. The report was peer reviewed by the scientific non-governmental ogranization (NGO), which judged the data to be reliable with rescriptions.

Data source

Reference

Reference Type:

review article or handbook

Title:

Unnamed

Year:

2007

Materials and methods

Study type:

cohort study (prospective)

Test guideline

Qualifier:

no guideline available

Principles of method if other than guideline:

measurement of thyroid gland size, serum measurements of thyroid hormone

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Hydrogen cyanide

EC Number:

200-821-6

EC Name:

Hydrogen cyanide

Cas Number:

74-90-8

Molecular formula:

CHN

IUPAC Name:

hydrogen cyanide

Details on test material:

Hydrogen cyanide is delivered as a component of cigarette smoke.

Results and discussion

Results:

Several scientists have studied goitre in European and African populations in relation to the thiocyanate level in serum and/or the urinary iodide excretion per day (Bourdoux et al, 1978; Cliff et al, 1986; Knudsen et al, 2000). Knudsen et al (2000) studied two Danish cohorts with different iodine excretion levels, both of which were iodide deficient. They observed a higher incidence of thyroid enlargement with decreasing urinary iodide excretion. Knudsen et al (2002) found an association between smoking and thyroid enlargement that was more pronounced at higher iodine deficiency. It is not possible to draw a simple correlation between the incidence of goitre and blood thiocyanate levels without considering the impact of dietary iodide. This general conclusion is consistent with the work of Hennart et al (1982), who suggested that thyroid effects were critically dependent on the ratio of iodine and thiocyanate intake and proposed that a urinary iodine­thiocyanate ratio (as μg Iodide ion/mg SCN ion) of greater than 4 would indicate no concern for thiocyanate­induced goitre.

The data of Knudsen et al (2002) seem to suggest that, in heavy smokers (> 30 ­ 40 cigarettes/d), serum thiocyanate levels of 150 ± 50 μmol/l led to an increase in thyroid size. In non­smokers, similar serum thiocyanate levels resulted in increases to about 14 ml in the case of a mild iodine deficiency and to 17 ml in the case of moderate iodine deficiency. The latter group would just reach the borderline of a normal adaptive response in the case of females (no gender differentiation was made in the publication). Interestingly, the authors also reported that the thyroid size in ex­smokers was approximately the same as in non­smokers, indicating reversibility of the effect.

Knudsen et al, 2002 has correlated increased incidences of thyroid enlargement to heavy smoking, in particular when combined with iodine deficiency. However, these studies often did not provide information on the corresponding thiocyanate levels.
Information on thiocyanate serum levels in smokers can be drawn from large studies that have determined serum thiocyanate concentrations in smokers and non­smokers in order to get an objective measure of cigarette consumption (Scheuermann et al, 1991 cited by Knudsen et al, 2000, 2002; Tsuge et al, 2000).


There is a high variation of serum thiocyanate in non­smokers (55 ± 30 μmol/l, Scheuermann et al, 1991 cited by Knudsen et al, 2002). This wide distribution means that the range of measured data is between 18 and 128 μmol/l serum (i.e. 2.5 and 97.5 percentile, respectively). This high variation obviously did not lead to thyroid malfunctioning. The reason for this high variation was probably related to diet.

Any other information on results incl. tables

The definition of goiterasused by different authors is not identical and has been a matter of debate. Thyroid enlargement is essentially an adaptive and reversible process. A pathological enlargement of thyroid is defined as 4 to 5 times the normal thyroid size. The technique of ultrasonography enables determination of the thyroid size more accurately in comparison with palpation and visible enlargement. Differences in volume of a few ml (10% to 20%) can be measured as a significant change. Nevertheless, if the thyroid is visibly enlarged with or without extended neck, the thyroid size has been increased by a factor of 4 to 5 and is called goitre (Delange 1999; Knudsen et al, 2002). Knudsen et al (2000) defined the diagnosis ‘thyroid enlargement’ by a thyroid volume of more than 25 ml in men and more than 18 ml in women.

 

Thiocyanate is a competitive inhibitor of iodide absorption by the thyroid. The effect of thiocyanate is compensated for by an increase in TSH release from the pituitary in order to maintain the appropriate T3 and T4 thyroid hormonelevelsin the blood. This isachievedby increasing the thyroid volume by increasing the thyrocyte volume.

In order to better define the borderline between adaptive and pathological changes in thyroid size in connection with thiocyanate exposure, the ECETOC Task Force compared the reported changes in thyroid size and related them to the serum thiocyanatelevelsand the iodine status. The normal thyroid size in a population with borderline iodine deficiency (70 μg iodide/l urine) was reported to be about 12 ml for men and 10 ml for women (Knudsen et al, 2000). Barrère et al (2000) observed a strong relation between thiocyanate level in the urine and the thyroid size in the healthy French population with borderline iodine deficiency. The thiocyanate level in serum was strongly related to smoking. These authors developed a regression equation which describes the increase of thyroid size with increasing urinary thiocyanate excretion under the condition of borderline iodine deficiency.

Thiocyanate is a competitive inhibitor of iodide absorption by the thyroid. The effect of thiocyanate is compensated for by an increase in TSH release from the pituitary in order to maintain the appropriate T3 and T4 thyroid hormone levels in the blood. This is achieved by increasing the thyroid volume by increasing the thyrocyte volume.

In order to better define the borderline between adaptive and pathological changes in thyroid size in connection with thiocyanate exposure, the ECETOC Task Force compared the reported changes in thyroid size and related them to the serum thiocyanate levels and the iodine status. Barrère et al (2000) observed a strong relation between thiocyanatelevelin the urine and the thyroid size in the healthy French population with borderline iodine deficiency. The thiocyanate level in serum was strongly related to smoking. These authors developed a regression equation which describes the increase of thyroid size with increasing urinary thiocyanate excretion under the condition of borderline iodine deficiency.

Itseemsthat small changes in iodide supply (assumed to be in equilibrium with urinary excretion)havea measurable impact on thyroid size. If the urinary iodide excretion is less than 20 μg/d, the incidence of goitre increases to more than 60%. The influence of thiocyanate on the thyroid size is marginal in comparison with lack of iodine. The data of Knudsen et al (2002) suggests that, in heavy smokers (> 30 ­ 40 cigarettes/d), serum thiocyanate levels of 150 ± 50 μmol/l led to an increase in thyroid size. In non­smokers, similar serum thiocyanatelevelsresulted in increases to about 14 ml in the case of a mild iodine deficiency and to 17 ml in the case of moderate iodine deficiency. The latter group would just reach the borderline of a normal adaptive response in the case of females(no gender differentiation was made in the publication).

Interestingly, the authors also reported that the thyroid size in ex­smokers was approximately the same as in non­smokers, indicating reversibility of the effect. The findings of Knudsen et al are in accordance with the data of Cliff et al (1986) who reported small adaptive changes in thyroid hormones, but no increased goitre incidence, in a cassava­eating non­iodine deficient population with serum levels of about 250 μmol SCNion/l (14.5 μg/ml). They also agree with the data of Barrère (2000), who reported an increased thyroid volume of 15.1ml in male French smokers (compared to 12.1 ml in non­ smokers) in a slightly iodine deficient population. According to the criteria above, this would also be regarded as an adaptive response rather than a pathological change.

Hennart et al (1982) suggested that thyroid effects of cyanide were critically dependent on the ratio of iodine and thiocyanate intake and proposed that a urinary iodine­thiocyanate ratio (as μg I ion/mg SCN ion) of greater than 4 would indicate no concern for thiocyanate­induced goitre.

However, the impact of an increase of thyroid size through thiocyanate exposure will depend on the size of the thyroid before exposure. If the thyroid is small, the increase of volume will not be visible. If, due to lack of iodine uptake, the volume of the thyroid is already 24 ml, then an increase in thyroid size of 25% will increase the volume to 30 ml, which would be diagnosed as a thyroid enlargement. So, increased thiocyanate in serum may increase the incidence of thyroid enlargement and ultimately of goitre at low iodine intake. In the case of sufficient iodine supply, the influence of increased thiocyanate will not result in malfunction of the thyroid pituitary axis. Hence, changes in thyroid size might be regarded as a physiological adaptation to variable levels of thiocyanate in blood.

 

Applicant's summary and conclusion

Conclusions:

This is an epidemiologic study which underscores the importance of baseline dietary iodine levels in susceptibility to cyanide­ associated goitre. Populations of unexposed Danes were monitored for their iodine and thiocyanate levels. The authors of the study found a wide distribution in the range of measured data, between 18 and 128 μmol/l serum (i.e. 2.5 and 97.5 percentile, respectively), in the unexposed population. This variation did not lead to thyroid abnormalities. Smoking about 30 ­ 40 cigarettes per day increased serum thiocyanate levels to 150 ± 50 μmol/l, and led to goitre development. However, a baseline deficiency of iodine was more critical to thyroid gland enlargement than was inhaled cyanide from cigarette smoking.